Nonalcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease, while there is still no medicine available. Farnesoid X receptor (FXR) is considered as a potential target for the treatment of NAFLD, and there are several FXR agonists reached in clinical trials. Based on better safety, industry and academia are pursuing development of the partial FXR agonists. To extend the chemical space of existing partial FXR agonists, we performed a structure-activity relationship study based on previously reported partial agonist 1 by using bioisosteric strategy. All of these efforts resulted in the identification of novel partial FXR agonist 13, which revealed the best agonistic activity in this series. Notably, compound 13 significantly alleviated the hepatic steatosis and hepatic function index in methionine-choline deficient (MCD) induced db/db mice, a classical nonalcoholic steatohepatitis (NASH) model widely used in preclinical evaluation. These results suggested that partial FXR agonist 13 might be a promising lead compound worthy further researches.

非酒精性脂肪性肝病（NAFLD）现在是最常见的慢性肝病，但仍然没有可用的药物。Farnesoid X受体（FXR）被认为是治疗NAFLD的潜在靶标，并且在临床试验中达到了几种FXR激动剂。基于更好的安全性，工业界和学术界正在开发部分FXR激动剂。为了扩展现有的部分FXR激动剂的化学空间，我们使用生物立体策略基于先前报道的部分激动剂1进行了结构-活性关系研究。所有这些努力导致鉴定了新颖的部分FXR激动剂13，其揭示了该系列中最好的激动活性。值得注意的是，化合物13显着减轻了蛋氨酸-胆碱缺乏（MCD）诱导的db / db小鼠的肝脂肪变性和肝功能指数，这是一种广泛用于临床前评估的经典非酒精性脂肪性肝炎（NASH）模型。这些结果表明，部分FXR激动剂13可能是有前途的铅化合物，值得进一步研究。